The objective of the proposed research is to measure the magnitude of and to understand the mechanisms underlying the radiobiologic effects produced by the decay of medically useful radionuclides. These include diagnostic nuclides that decay by electron capture and isomeric transition (e.g. 99mTc, 111In, 123I), and promising therapeutic ones that decay by Auger-electron and alpha-particle emission (e.g. 123I, 125I, 211At, 213Bi). Specifically, we intend to (i) use computational modeling methods to examine the nature of the interactions between molecules labeled with these radionuclides and their targets, thereby developing more rational approaches to the synthesis of radiolabeled molecules for cancer therapy, (ii) explore the biophysical processes underlying damage to DNA (naked to higher order) caused by the decay of these radionuclides and elucidate whether these are a consequence of direct or indirect mechanisms, (iii) associate radionuclide- decay-induced apoptosis with the physical decay characteristics of these radionuclides and their site of decay, cell type, and cell radiosensitivity, (iv) investigate the factors and mechanisms underlying the induction of inhibitory (125I) and stimulatory (123I) bystander effects, (v) quantify the upregulation of cancer-induction-related gene expression in mouse lung cells irradiated in vivo with noncytocidal and cytocidal doses as well as in bystander mouse lung cells, and (vi) establish the therapeutic efficacy of selected radiolabeled molecules in tumor-bearing animals. PUBLIC HEALTH RELEVANCE The relationship between the intracellular localization of low-energy electron- and alpha-particle- emitting radionuclides and the biologic consequences of the resulting microdistribution of energy has practical considerations for both defining the risks associated with the use of radionuclides in nuclear medicine and assessing the potential of such radionuclides for cancer therapy. We envisage that the multidisciplinary approach proposed in this project (i.e. use of computational modeling methods to predict the nature of interactions between the radiolabeled molecules and DNA, exploration of the biophysical processes responsible for DNA damage, identification of the pathways mediating cell death and the bystander effect, and quantification of the alterations in cancer-induction genes) will help to determine many of the factors underlying the radiobiologic effects of these radionuclides and, thereby, to assess possible detrimental effects.